Title; Effect of Gallium on Bone The major objective of this continuation application is to study the effects of gallium, a group IIIa meal, on bone metabolism. The studies proposed are a logical extension of our previous work showing gallium to be a safe and highly effective agent for the treatment of hypercalcemia of malignancy. Our hypothesis is that gallium blocks bone resorption and enhances bone formation by favorably altering the function of bone cells (osteoclasts and osteoblasts) as well as physicochemically altering mineral properties. The purpose of the proposed experiments is to demonstrate that all these mechanisms contribute to the beneficial effects of gallium on bone metabolism. Our approach towards this objective will be to apply physical and biochemical methods to a panel of synthetic, cell and organ culture systems as well as in vivo models in order to study isolated aspects of bone metabolism in depth. Specific experiments include the use of a synchrotron generated energy source to localize at the microscopic and atomic levels, the trace of gallium that are present in the bone matrix. In vitro, cell-mediated mineral formation and growth will be measured. Bone collagen synthesis will be studied using bone rudiments, osteoblast cell cultures and a rodent model. Gene-regulation of osteocalcin (bone-Gla protein) will be examined using specific cDNA probes. In vivo, bone mineralization and remodeling will be studied using mineralized and demineralized bone implants. The biomechanical properties of rat bones will be tested to evaluate the strength of bone produced in the presence of gallium. These proposed studies are meant to provide insights into the mechanisms of action of gallium in bone. In addition, they provide a basis for the design and realization of future clinical trials with this therapeutically useful new agent.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA038645-06
Application #
3176783
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Project Start
1985-07-01
Project End
1993-04-30
Budget Start
1990-05-01
Budget End
1991-04-30
Support Year
6
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Hospital for Special Surgery
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10021
Guidon Jr, P T; Salvatori, R; Bockman, R S (1993) Gallium nitrate regulates rat osteoblast expression of osteocalcin protein and mRNA levels. J Bone Miner Res 8:103-12
Donnelly, R; Bockman, R; DiCarlo, E et al. (1993) The effect of gallium nitrate on healing of vitamin D- and phosphate-deficient rickets in the immature rat. Calcif Tissue Int 53:400-10
Bockman, R S; Guidon Jr, P T; Pan, L C et al. (1993) Gallium nitrate increases type I collagen and fibronectin mRNA and collagen protein levels in bone and fibroblast cells. J Cell Biochem 52:396-403
Salvatori, R; Guidon Jr, P T; Rapuano, B E et al. (1992) Prostaglandin E1 inhibits collagenase gene expression in rabbit synoviocytes and human fibroblasts. Endocrinology 131:21-8
Donnelly, R; Bockman, R S; Doty, S B et al. (1991) Bone particles from gallium-treated rats are resistant to resorption in vivo. Bone Miner 12:167-79
Bockman, R S; Repo, M A; Warrell Jr, R P et al. (1990) Distribution of trace levels of therapeutic gallium in bone as mapped by synchrotron x-ray microscopy. Proc Natl Acad Sci U S A 87:4149-53
Weinerman, S A; Bockman, R S (1990) Medical therapy of osteoporosis. Orthop Clin North Am 21:109-24
Bockman, R S; Weinerman, S A (1990) Steroid-induced osteoporosis. Orthop Clin North Am 21:97-107
Warrell Jr, R P; Bosco, B; Weinerman, S et al. (1990) Gallium nitrate for advanced Paget disease of bone: effectiveness and dose-response analysis. Ann Intern Med 113:847-51
Bockman, R S; Warrell Jr, R P; Levine, B et al. (1990) Trace elemental analysis in bone using x-ray microscopy. Basic Life Sci 55:293-6

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